Relationship of Body Mass Index with Prognosis in Breast Cancer Patients Treated with Adjuvant Radiotherapy and Chemotherapy

Breast cancer is the most common malignant disease among women and second leading cause of cancer-related deaths (Siegel et al., 2012; Wu et al., 2014). American Cancer Society (ACS) estimates that 29% of all newly diagnosed malignant disease will be breast cancer and it will be cause in 16% of the deaths (Parekh et al., 2012; Siegel et al., 2012; Taghavi et al., 2012). Increased number of survivors after diagnosis of breast cancer suggests that modifiable risk factors that can improve remission, survival and quality of life should have to be investigated (Malcolm et al., 2009; Klimant et al., 2011). It has been thought that obesity may be one of the independent risk factors in patients with breast cancer. In recent studies, a negative correlation was identified between body mass index (BMI) and progression-free and overall survival times in patients with early breast cancer. However, it hasn’t been clarified whether obesity affects patients with breast cancer independently (Ryu et al., 2001; Protani et al., 2010; Alegre et al., 2013; Suleeporn et al., 2013; Ladoire et al., 2014).


Introduction
Breast cancer is the most common malignant disease among women and second leading cause of cancer-related deaths (Siegel et al., 2012;Wu et al., 2014).American Cancer Society (ACS) estimates that 29% of all newly diagnosed malignant disease will be breast cancer and it will be cause in 16% of the deaths (Parekh et al., 2012;Siegel et al., 2012;Taghavi et al., 2012).Increased number of survivors after diagnosis of breast cancer suggests that modifiable risk factors that can improve remission, survival and quality of life should have to be investigated (Malcolm et al., 2009;Klimant et al., 2011).It has been thought that obesity may be one of the independent risk factors in patients with breast cancer.In recent studies, a negative correlation was identified between body mass index (BMI) and progression-free and overall survival times in patients with early breast cancer.However, it hasn't been clarified whether obesity affects patients with breast cancer independently (Ryu et al., 2001;Protani et al., 2010;Alegre et al., 2013;Suleeporn et al., 2013;

Patient group and demographic characteristics
We retrospectively reviewed operated breast cancer patients who were followed in Radiation Oncology department of Kayseri Teaching Hospital between 2005 and 2013.Patients with missing data and those lost in followup were excluded from analysis.The study was planned in accordance to local ethics regulations and Helsinki Declaration.We reviewed age, gender, menopausal status, family history of breast cancer, height, weight, BMI, tumor localization, tumor stage, surgery type, histopathological findings, data regarding chemotherapy and radiotherapy, and survival times.In the histopathological diagnosis, tumor type, tumor localization, tumor diameter, lymphatic metastasis, number of lymph nodes excised, number of lymph nodes with metastatic infiltration, level of estrogen and progesterone receptors, cerb-B2 status, grade, and lymphovascular and perineural invasion status were recorded.
Weight and height measurements were performed to determine body mass index.BMI categories were defined according to World Health Organization criteria as follows: BMI<18.5 kg/m 2 as underweight; 18.5-24.9kg/ m 2 as normal weight; 25.0-29.9kg/m 2 as grade 1 obesity; 30.0-39.9 kg/m 2 as grade 2; and ≥40 kg/m 2 as grade 3 obesity.

Treatments
Surgery: all patients underwent abdominal sonography, mammography, complete blood count, biochemical evaluations and posterioanterior chest radiography before surgery.Fine-needle aspiration biopsy or excisional biopsy was performed to mass.After biopsy, modified radical mastectomy (MRM) and breast-conserving surgery (BCS) were performed as surgical therapy.After surgery, staging was performed based on histopathology results by using American Joint Committee on Cancer (AJCC) 2002 staging system.
Adjuvant chemotherapy: decision regarding postoperative chemotherapy and/or hormone therapy was made by considering performance status, biological age, and comorbid diseases.Chemotherapy was given to patients with tumor diameter >1 cm or axillary lymph node ≥1-positive, those with ECOG (Eastern Cooperative Oncology Group) performance status 0-2, those having no severe cardiac problem, and those with normal renal and bone marrow functions.Chemotherapy schedules included one of the following: CMF (Cyclophosphamide, Methotrexate, 5-Flurouracyl), CAF (Cyclophosphamide, Doxorubicin, 5-Flurouracyl), CEF (Cyclophosphamide, Epirubicin, 5-Flurouracyl), AC (doxorubicin, cyclophosphamide) or docetaxel.
Adjuvant radiotherapy: radiotherapy was given to the patients with tumor diameter >5 cm, insufficient lymph node dissection, axillary lymph node positivity ≥3, and those underwent BCS.Total dose was 50-60 Gy in patients underwent MRM, while 60-66 Gy in those underwent BCS.Firstly, radiotherapy was delivered to whole breast and/or peripheral lymphatics with a dose of 46-50 Gy in all patients underwent BCS.Then, additional electron doses of 10-16 Gy with appropriate energy levels were delivered to metallic clips, incision scar and excision pouch detected by sonography with a margin of 1 cm.For patients with MRM, additional doses of 10 Gy were given to cases with skin invasion and extra-capsular invasion.
Adjuvant hormone therapy: hormone therapy was given to the patients with positive estrogen and/or progesterone receptors.Tamoxifen and/or LHRH analogs were given to premenopausal patients while tamoxifen or aromatase inhibitors were given to postmenopausal patients for 5 years.

Follow-up
Follow-up visits were scheduled by 3-months interval within first year; biannually until end of year 5; and annually thereafter.Complete blood count, biochemical parameters, and Ca 15-3 and CEA levels were measured biannually, while chest radiographs, mammography, abdominal sonography and bone scintigrapy were obtained annually.

Statistical analysis
Statistical analysis was performed by using SPSS for Windows 13.0 (Statistical Package for the Social Sciences, Chicago, IL).Descriptive statistics including minimum-maximum, mean, standard deviation and percentages were used in data analysis.In comparative studies, One-Sample Kolmogorov-Smirnov test was used to evaluate normal distribution.In groups, t test was used to assess quantitative data with normal distribution while Mann Whitney U test was used to assess quantitative data with skewed distribution.Progression-free survival was defied as the time from surgery to local or distant relapse.Overall survival was defined as time from surgery to death in non-survivors and time from surgery to last control in survivors.Five-and 10-years survival rates were calculated by using survival tables.In univariate analysis, Kaplan-Meier curves were compared by using Log-Rank method.p<0.05 was considered as statistically significant.
In cases with breast cancer, the relationship between BMI and other prognostic factors were investigated by using Pearson chi-square test.BMI was between 30.0-39.9 kg/m 2 in 192 patients, 18.5-24.9kg/m 2 in 112 patients, and 25.0-29.9kg/m 2 in 112 patients.BMI was higher than 25.0 kg/m 2 in 343 of 456 patients.Significant correlations were detected between BMI and menopausal status (p=0.029),histological type (p<0.000),chemotherapy DOI:http://dx.doi.org/10.7314/APJCP.2014.15.10.4233 BMI is a Predictor of Survival in Breast Cancer Patients Treated with Adjuvant Radiotherapy and Chemotherapy (p=0.003) and hormone therapy (p=0.014).Follow-up was ranging from 4.8 and 195 months.During followup, 48 patients died due to disease (n=22) or non-related causes (n=26; cardiovascular disease, senility, renal tumor, cerebrovascular disease etc.) Local recurrence or distant metastasis was detected in 72 cases.There was multiple-organ metastasis in 26 cases, bone metastasis in 24 cases, pulmonary metastasis in 10 cases and other organ metastasis in 12 cases.

Discussion
Up to date, although many studies have been conducted about relationship between breast cancer and obesity, and many proposals have been made, it has been failed to establish that obesity plays a role as a primary etiological factor.However, some suggestive evidence has been revealed as a result of these intensive investigations.Although an increased risk by increasing body weight has been reported in preliminary studies investigating relationship between body weight and breast cancer, it was emphasized that further comprehensive studies are needed to draw conclusion about this finding in the recent studies.In terms of breast cancer, it was shown that low body weight increases risk during premenopausal period, while increased body weight increases risk during postmenopausal period.As a result, investigators began to evaluate prognostic value of obesity in breast cancer, DOI:http://dx.doi.org/10.7314/APJCP.2014.15.10.4233 BMI is a Predictor of Survival in Breast Cancer Patients Treated with Adjuvant Radiotherapy and Chemotherapy since available studies suggested a small but significant relationship between obesity and risk for breast cancer.(Petrelli et al., 2002;Sestak et al., 2010;Klimant et al., 2011;Suleeporn et al. 2013).
In our study, significant correlations were detected between BMI and menopausal status, histological type, chemotherapy and hormone therapy.It has been thought that many metabolic and hormonal pathways are involved in the relationship between obesity and prognosis.In premenopausal women, the estradiol is the predominant estrogen, while, in postmenopausal women, estrone is main estrogen source, which is produced from androstenedion through aromatization in the presence of aromatase enzyme in fat tissue.It is thought that increased serum estrogen play role in induction and progression of breast cancer by increasing frequency of DNA mutations via stimulation of cell division and triggering growth of estrogen-dependent tumors.In addition, levels of sex-hormone binding globulin are also decreased in these patients.Given that obesity may be a component of metabolic syndrome causing insulin resistance, hyperinsulinemia developed in obesity may lead poorer prognosis in patients with breast cancer through insulinlike growth factor-1 (IGF-1) (Petrelli et al., 2002;Protani et al., 2010;Goodwin 2013;Suleeporn et al. 2013).In recent studies, a negative correlation was detected between obesity and survival in patients diagnosed as early stage breast cancer.There is substantial evidence suggesting that higher BMI (>25 kg/m 2 ) is associated with worse outcome in patients with breast cancer.This is also true for specific subgroups including women with locally advanced breast cancer and postmenopausal women.Although there is controversy in literature, it was reported that hormone therapy was less effective in women with higher BMI.There are several randomized studies comparing AIs and tamoxifen in adjuvant treatment of breast cancer effects of BMI on relative effectiveness of AI and tamoxifen were reported in four of these studies (ATAC, BIG 1-98 and TEAM in the postmenopausal setting and ABCSG-12 in the premenopausal setting).ATAC and BIG 1-98 but not TEAM study confirmed obesity as a negative prognostic factor; in addition, obesity was associated with poor outcomes in anastrozole arm in ABSCG-12 study (Sestak et al., 2010;Ewertz et al., 2011;Goodwin 2013).In a study on 4996 patients with node-positive breast cancer, Ladoire et al. reported that endocrine treatment didn't modified effect of obesity on tumor prognosis (Ladoire et al., 2014).In a study by Griggs et al., it was reported that obese patients were more likely to receive reduced doses of chemotherapy compared to normal weight women, which was associated with poor prognosis (Griggs et al., 2005).In the study by Ladoire et al., it was reported that obesity remained to be associated with poorer baseline tumor characteristics but had no effect on the prognosis when modern adjuvant chemotherapy was delivered at appropriate doses (Ladoire et al., 2014).
In our study, 343 of 456 patients were in obesity group with a BMI >25 kg/m 2 .It was found that OS was significantly higher in the group with normal BMI when compared to those in the underweight and obese patient groups.It was found that the factors significantly associated with OS were stage, tumor diameter, lymph node metastasis and BMI.In many studies, there are strong evidence suggesting that disease-free and overall survival times were significantly decreased by increasing BMI.These findings were attempted to be explained by different risk factors (de Azambuja et al., 2010;Protani et al., 2010;Ewertz et al., 2011;Alegre et al., 2013;Ladoire et al., 2014).In the study, de Azambuja et al. (2010) retrospectively evaluated 2887 patients with node-positive breast cancer who were enrolled to Breast International Group (BIG) 02-98 study.Authors reported that obesity is a negative prognostic factor affecting both PFS and OS (de Azambuja et al., 2010).Again, in the study by Petrelli et al., it was reported that mortality was higher in morbid obese postmenopausal women with breast cancer compared to those with normal BMI.In a study on 605 patients with breast cancer, disease-free and overall survivals were found to be shorter in underweight patients when compared to other groups (Petrelli et al., 2002).In a meta-analysis by Ryu et al., it was found that obesity at diagnosis was associated with poorer prognosis (Ryu et al., 2001).In contrast, some studies suggested that BMI had no effect of DFS but it had significant negative effect on OS.In a study on 6972 patients with early stage breast cancer, Berclaz et al. investigated effect of BMI on survival.Authors combined normal and underweight groups because of smaller sample size.In conclusion, they reported that OS was found to be higher in patients with normal BMI when compared to overweight or obese patients (p=0.03),whereas BMI had no effect on PFS (Berclaz et al., 2004).In a study on 418 patients with triple-negative breast cancer, Ademuyiwa et al. reported that BMI had no effect on either OS or PFS (Ademuyiwa et al., 2011).Our results were in agreement with those of Marret et al., Berclaz et al., and Petrelli et al. regarding overall survival.In our study, smaller sample size, genetic characteristics of patient population and potential body weight changes during follow-up can explain our results regarding PFS.In future, interactions of BMI with other prognostic factors such as blood parameters, clinical factors and receptor levels need to be established (Elgin et al., 2013;Olmez et al., 2013;Tanriverdi et al., 2014).
In conclusion, in our study, it was found that overall survival was shorter in patients with BMI<18.5 kg/m 2 or >25.0 kg/m 2 when compared to other patient groups.In addition, it was also found that progression-free survival was shorter but the difference didn't reach statistical significance.We think that this finding could be due to small sample size.These findings should be further tested in comprehensive studies.